The present invention is in the field of human medicine, particularly in the treatment of diabetes and hyperglycemia by the administration of monomeric insulin analogs. More specifically, the present invention relates to formulations of monomeric insulin analogs that have superior long-term physical stability when exposed to high mechanical energy input and high temperature.
Stable formulations of therapeutic agents are particularly required for use in delivery devices that expose these agents to elevated temperatures and/or mechanical stress. For example, stable insulin formulations are required for use in continuous infusion systems and pen delivery devices. Current formulations provide only limited stability in these types of delivery devices.
In continuous infusion systems, a fluid containing a therapeutic agent is pumped from a reservoir, usually to a subcutaneous, intravenous, or intraperitoneal depot. The reservoir, which must be refilled periodically, is attached to the patient's body, or is implanted in the patient's body. In either case, the patient's body heat and body motion, plus turbulence in the tubing and pump impart a relatively high amount of thermo-mechanical energy to the formulation. In the interest of minimizing the frequency with which the reservoir is refilled, and of minimizing the size of the reservoir, formulations having a relatively high concentration of the therapeutic agent are highly advantageous.
Massey and Sheliga, U.S. Pat. No. 4,839,341 (Eli Lilly and Company, 1989) discuss the challenges involved in providing stable insulin formulations for continuous infusion, and present a thorough review of the art through about 1984. The challenges are even greater at the present time because insulin formulations that are stable for 1 to 3 months are now demanded.
Injector pens have also been developed to aid diabetics in measuring and administering an accurate and controlled dose of insulin. Generally, these pens are secured onto a cartridge having a particular quantity of liquid medication sealed therein. The cartridge includes a plunger and a mechanism for advancing the plunger in the cartridge in such a manner to dispense the medication. Injector pens may be reusable or disposable. In reusable pens, a user can change a spent cartridge and reset the leadscrew of the pen back to its initial position. In a disposable pen, the cartridge is permanently captured in the pen which is disposed of after the contents of the cartridge have been exhausted. Formulations of insulin used in these pens are exposed to physical stress and limited stability is usually observed.
With the introduction of new monomeric insulin analogs for the treatment of diabetes, there is a need to utilize these compounds in treatment regimes that can compromise the inherent stability of the formulations. Rapid-acting insulins, known as monomeric insulin analogs, are well-known in the art, and are disclosed in Chance, et al. U.S. Pat. No. 5,514,646, issued May 7, 1996; Brems, et al., Protein Engineering, 6:527-533 (1992); Brange, et al:, EPO publication No. 214,826 (published Mar. 18, 1987); and Brange, et al., Current Opinion in Structural Biology 1:934-940 (1991). Monomeric insulin analogs are absorbed much faster than is insulin, and are ideally suited for postprandial control of blood glucose levels in patients in need thereof. They are also especially well-suited for administration by continuous infusion for both prandial and basal control of blood glucose levels because of their rapid absorption from the site of administration.
Unfortunately, monomeric insulin analog formulations have a propensity to aggregate and to become unstable when exposed to thermo-mechanical stress [Bakaysa, et al., U.S. Pat. No. 5,474,978, issued Dec. 12, 1995]. Aggregation may even be manifested as precipitation of higher-order insulin species. In this way, aggregation can prevent reproducible delivery of effective therapeutic doses of monomeric insulin analogs, and may also cause irritation at the administration site or a more systemic immunological response. Insulin analog formulations stabilized against aggregation are desirable.
Formulations of monomeric insulin analogs for use in continuous infusion systems must remain soluble and substantially free of aggregation, even though subjected to the patient's body heat and motion for periods ranging from a few days to several months. Instability is promoted by the higher protein concentrations that are desirable for continuous infusion systems and by the thermo-mechanical stress to which formulations are exposed in continuous infusion systems. Therefore, improvement in the physical and chemical stability of concentrated insulin analog formulations is urgently needed to permit them to be used successfully in continuous infusion systems. Improvement in the stability of monomeric insulin formulations for uses other than in continuous infusion is also beneficial.
Stabilized formulations of monomeric insulin analogs that are fast-acting, are known. Bakaysa, et al., U.S. Pat. No. 5,474,978 disclose and claim a human insulin analog complex comprising six molecules of a human insulin analog (hexamer complex), two zinc atoms, and at least three molecules of a phenolic preservative, formulations comprising the hexamer complex, and methods of treating diabetes mellitus by administering the formulation. Bakaysa, et al., also claim formulations of the hexamer complex further comprising an isotonicity agent and a physiologically tolerated buffer.
The specification of U.S. Pat. No. 5,474,978 discloses that the zinc complexes of monomeric insulin analogs may be formulated in the presence of a “physiologically tolerated buffer.” Among the buffers mentioned for use in formulations are sodium phosphate, sodium acetate, sodium citrate, and TRIS. The examples in U.S. Pat. No. 5,474,978 only describe formulations wherein the buffer is sodium phosphate, and only sodium phosphate buffer is required in a claim (claim 5). None of the examples in U.S. Pat. No. 5,474,978 specifically disclose the use of TRIS buffer in formulations of zinc-monomeric insulin analog complexes.
Monomeric insulin analog formulations containing protamine have also been developed to yield, upon use, an intermediate duration of action. Monomeric insulin analog-protamine formulations are described in U.S. Pat. No. 5,461,031. Methods for crystallizing monomeric insulin analogs with the basic peptide protamine to yield a neutral protamine suspension are known in the art. In addition, biphasic mixtures containing a monomeric insulin analog solution and a monomeric insulin analog-protamine suspenion can be prepared. These mixtures have the optimal time-action properties of the analogue in combination with basal activity. Monomeric insulin analog mixtures are also described in U.S. Pat. No. 5,461,031.
Monomeric insulin analog-protamine suspension formulations and biphasic mixtures are suitable for use in cartridge container presentations. Yet, because these devices require frequent patient manipulation, increased stress to the preparation results. Protamine salt formulations in particular have limited stability when exposed to thermomechnical stress. Thus, there is a need to develop stable intermediate acting monomeric insulin analog-protamine formulations as well as biphasic mixture formulations.
We have now discovered that when certain physiologically tolerated buffers other than phosphate are employed in formulations of zinc-monomeric insulin analog complexes, protamine salt formulations, or biphasic mixtures of monomeric insulin analog, the physical stability of the formulations is unexpectedly and considerably greater than when phosphate buffer is used. Most advantageous is our discovery that, whereas, soluble formulations of zinc-monomeric insulin analog complexes with a phosphate buffer, such as those specifically exemplified in U.S. Pat. No. 5,474,978, are not physically stable enough for long-term administration using continuous infusion pumping systems, the soluble formulations provided by the instant invention are sufficiently stable to be used with safety for long periods of insulin infusion. We have also discovered that the addition of arginine to protamine salt formulations of monomeric insluin analogs results in dramatic improvements in both the chemical and physical stability of the formulation.